Persistent and/or dysregulated macrophage activation plays a key role in the pathogenesis of multiple inflammatory lung diseases, including chronic obstructive pulmonary disease (COPD). Imaging activated macrophages using a non-invasive approach would allow frequent monitoring of disease progression and response to therapy. In the first phase of this RFA, we focused on developing optical and nuclear imaging strategies based on expression of folate receptor ? (FR?) by activated macrophages. In the setting of lung inflammation, we showed markedly increased FR? expression in macrophages and monocytes that co- expressed high levels of inflammatory cytokines. In preliminary data, we showed that chronic airway inflammation in COPD results in a dramatic increase in FR?-expressing macrophages. In lung macrophages obtained by bronchoalveolar lavage (BAL) from COPD patients, approximately 50% express FR?, whereas only <10% of macrophages from healthy controls express FR?. In this proposal, we will test the hypothesis that folate-based molecular imaging using positron emission tomography (PET) to detect activated macrophages can identify COPD patients and determine those most likely to have rapid disease progression due to higher levels of chronic lung inflammation. Specific aims are designed to: 1) validate folate-based PET probes in mouse models of COPD, 2) perform dosing, toxicology, and safety studies with folate-based PET probes in rodents and humans, and 3) test whether folate-based PET imaging can be used to identify COPD patients and determine whether the PET signal correlates with measurements of inflammation, disease severity, and rate of disease progression. Initial studies will optimize our current folate-PET probes and determine whether PET imaging of activated macrophages can be used to identify progression of disease in mouse models of COPD. Subsequently, dosing and toxicology studies will be performed in rodents and humans, followed by a Phase I study in humans comparing individuals with COPD to control subjects without lung disease. For this investigation, we will partner with an ongoing EDRN-sponsored study designed for longitudinal evaluation of a cohort at risk for lung cancer. PET imaging will be performed prior to scheduled bronchoscopy, which is completed as part of the follow-up evaluation in this cohort. Imaging data will be correlated with parameters of inflammation in BAL and physiologic measurements of disease severity and progression. Together, these studies will determine whether folate-based imaging is useful for quantifying inflammation in lung diseases like COPD, and whether identifying macrophage activation could delineate a subgroup of patients who would benefit from anti-inflammatory or macrophage-targeted therapies. (End of Abstract)